Ts Cheng

Abnormal diffusion tensor in nonsymptomatic familial amyotrophic lateral sclerosis with a causative superoxide dismutase 1 mutation

To determine whether diffusion abnormalities can be observed in nonsymptomatic family members with a known causative Cu/Zn superoxide dismutase mutation (asymptomatic familial amyotrophic lateral sclerosis; AFALS+SOD1) in a family with autosomal dominant familial amyotrophic lateral sclerosis (ALS) using diffusion tensor imaging (DTI).

Bath‐related headache

Bath-related headache (BRH) is a rare primary headache syndrome. We present our experience over seven years and review all reported cases of BRH. Thirteen patients, including six from our group, are described. BRH occurred exclusively in middle-aged or elderly Oriental women (mean age 51 years, range 32-67. Hong Kong 6 cases, Taiwan 4 cases, Japan 3 cases). The typical presentation was a uniphasic cluster of severe headache recurrently triggered by bathing or other activities involving contact with water. Each attack lasted 30 min to 30 h. Onset was hyperacute, consistent with that of thunderclap headache. Reversible multisegmental cerebral vasoconstriction was found in two patients. No underlying secondary causes were identified. Response to acute treatment was generally unsatisfactory, but headache could be prevented by avoiding the specific trigger(s). BRH runs a self-limiting course; all patients remitted within three months after onset. Nimodipine may shorten the duration of illness.

Wilson’s disease with depression and parkinsonism

Wilsons disease (WD) is an autosomal recessive disorder with reduced biliary excretion of copper plus impaired formation of ceruloplasmin, leading to copper accumulation in the liver, brain, kidney, and cornea. Clinical manifestations include liver damage, psychiatric symptoms, and neurological features. We report a 35-year-old woman with a history of deranged liver functions who had severe depression several years later and eventually presented with parkinsonian features. The underlying diagnosis is WD and family screening revealed WD in 2 other siblings. She could not tolerate penicillamine because of fever and leucopenia. While taking trientine hydrochloride and zinc sulphate, her parkinsonism improved and her depression remained in remission. WD should be considered in patients with unexplained liver function derangement or psychiatric symptoms. Early diagnosis and initiation of specific treatment are crucial in minimising any further cerebral and hepatic damage as well as securing possible improvement in organ functions.

−459C>T point mutation in 5′ non‐coding region of human GJB1 gene is linked to X‐linked Charcot‐Marie‐Tooth neuropathy

Abstract  Charcot‐Marie‐Tooth (CMT) neuropathy is inherited with genetic and clinical heterogeneity. The X‐linked form (CMTX) is linked to mutations in the GJB1 gene. However, the genotype‐phenotype correlation between variants in the non‐coding region of GJB1 gene and CMTX is unclear. We found two structural variants (−459C>T and −713G>A) in the 5′ non‐coding region of a transcript (Ref seq ID: NM_000166) of the GJB1 gene and explored its association with CMTX in two Chinese families. All family members who carried the −459C>T variant either were symptomatic or had abnormal electrophysiological studies compatible with CMTX, whereas all the non‐symptomatic family members who had normal electrophysiological studies and 10 healthy unrelated controls did not have this variant. The other variant in the 5′‐flanking region of the gene was found to be a benign polymorphism, although it had been earlier reported to be associated with CMTX in a Taiwanese family. Secondary structure prediction analysis of mutant mRNA using Mfold and RNAstructure softwares indicates that the −459C>T mutation may reduce translation efficiency of the GJB1 gene by changing its 5′‐untranslated region secondary structure and abolishing the internal ribosome entry site at the initialization of its translation in Schwann cells. Our study can help clarify the causal mutations of CMTX in the non–protein coding region of GJB1.

Clinical phenotypes of a large Chinese multigenerational kindred with autosomal dominant familial ALS due to Ile149Thr SOD1 gene mutation

About 10% of amyotrophic lateral sclerosis (ALS) cases are familial. We identified a five‐generation Chinese family with autosomal dominant familial ALS (FALS). We performed a detailed family study, clinical and electromyographic validation, and SOD1, VEGF and CNTF mutation analyses. Forty‐five living members (16 affected) were studied and DNA samples collected. Genealogical data were collected for deceased members. Based on the duration between symptom onset to ventilator dependence, they were divided into rapidly progressive (range 1–18 months, mean (SD) duration = 12.08 (±6.10) months, mean (SD) age of symptom onset = 39.75 (±9.84) years) and slowly progressive groups (>18 months; mean (SD) age of onset = 37.25 (±5.32) years old). We identified a heterozygous mutation of ATT to ACT of SOD1 gene at codon 149 in exon 5 resulting in substitution of isoleucine to threonine. It co‐segregated with all affected members and 11 non‐symptomatic members. We report a large multigenerational Chinese FALS kindred with I149T mutation in SOD1. No polymorphisms or mutations were found to date in two known modifier genes, namely, VEGF and CNTF, which were associated with heterogeneity in the phenotype within this kindred. Follow‐up of the family will be helpful to explore any potential disease markers.